Alternative exon definition events control the choice between nuclear retention and cytoplasmic export of U11/U12-65K mRNA

Cellular homeostasis of the minor spliceosome is regulated by a negative feed-back loop that targets u11-48k and u11/u12-65k mrnas encoding essential components of the u12-type intron-specific u11/u12 di-snrnp. this involves interaction of the u11 snrnp with an evolutionarily conserved splicing enhancer giving rise to unproductive mrna isoforms. in the case of u11/u12-65k,this mechanism controls the length of the 3′ untranslated region (3′utr). we show that this process is dynamically regulated in developing neurons and some other cell types,and involves a binary switch between translation-competent mrnas with a short 3′utr to non-productive isoforms with a long 3′utr that are retained in the nucleus or/and spliced to the downstream amylase locus. importantly,the choice between these alternatives is determined by alternative terminal exon definition events regulated by conserved u12- and u2-type 5′ splice sites as well as sequence signals used for pre-mrna cleavage and polyadenylation. we additionally show that u11 snrnp binding to the u11/u12-65k mrna species with a long 3′utr is required for their nuclear retention. together,our studies uncover an intricate molecular circuitry regulating the abundance of a key spliceosomal protein and shed new light on the mechanisms limiting the export of non-productively spliced mrnas from the nucleus to the cytoplasm. © 2017 verbeeren et al.